Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis

Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of β-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism.     

Clinical and molecular analysis of isovaleric acidemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD). Accumulation of isovaleryl-CoA derivatives to toxic levels results in clinical symptoms of the disease. Here, we investigate the clinical and molecular features of Arab patients with IVA. Patients from five unrelated families were evaluated clinically and for defects in the IVD gene. Four novel mutations (p.F382fs, p.R392H, p.R395Q and p.E408K) have been identified with p.R395Q occurring in two families. In addition, molecular modeling of the identified missense mutations predicted their damaging effects on the protein and computational analysis of the p.F382fs mutation predicted the disruption of a 3′ splicing site resulting in inactive or unstable gene product. Furthermore, we found an unusual case of a 17 years old female homozygous for the p.R392H mutation with no clinical symptoms. Our results illustrate a heterogeneous mutation spectrum and clinical presentation in the relatively small UAE population.     

Stüve-Wiedemann syndrome and related bent bone dysplasias

Stüve-Wiedemann syndrome (SWS) is a severe congenital skeletal dysplasia associated with life threatening dysautonomic manifestations. Newborns affected with this condition exhibit distinctive shortening and bowing of the long bones with reduced bone volume. The majority of affected newborns die early due to neuromuscular complications namely hyperthermia, apnea, and swallowing difficulties. In this review, we provide an overall picture on the clinical, including long-term management, molecular and cellular aspects of SWS and discuss briefly other related bent bone dysplasias.     

Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE)

The United Arab Emirates inhabitants are ethnically diverse, with ancestries from Arabia, Persia, Baluchistan, and Africa. However, the majority of the current five million inhabitants are expatriates from the Asian subcontinent, Middle Eastern, African, and European countries. Consanguineous marriages within most UAE subpopulations are still the norm, leading to the formation of isolates and higher frequencies of recessive conditions. The UAE is ranked sixth in terms of prevalence of birth defects, with more than 270 genetic disorders reported in the national population. The UAE has high frequencies of blood disorders including thalassemias, sickle cell disease, and G6PD. In addition, certain genetic conditions are relatively common including cystic fibrosis, Joubert, and Meckel syndromes. Furthermore, numerous rare congenital malformations and metabolic disorders have been reported. We review the single gene disorders that have been studied at the molecular level in the UAE (which currently stand at 76) and compile the mutations found. Several novel (p.S2439fs) mutations have been reported including c.7317delA in NF1, c.5C>T (p.A2V) in DKC1, c.1766T>A (p.I589N) in TP63, and c.2117G>T (p.R706L) in VLDLR. We hope that this review will form the basis to establish a UAE mutations database and serve as a model for the collection of mutations of a country. Hum Mutat 31:505–520, 2010. © 2010 Wiley‐Liss, Inc.     

Are the strokes in moyamoya syndrome associated with Down syndrome due to protein C deficiency?

Moyamoya syndrome has occasionally been seen in association with Down syndrome. We report a child with moyamoya syndrome and Down syndrome who was admitted with repeated episodes of strokes; his magnetic resonance imaging and magnetic resonance angiography findings confirmed the presence of occlusive cerebrovascular disease with basal collateral vessels. His protein C levels were significantly decreased during the stroke. Complete clinical recovery was seen during follow-up. This raises the possibility of a link between protein C deficiency and Down syndrome with moyamoya syndrome.     

Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux

Natriuretic peptides (NPs) comprise a family of structurallyrelated but genetically distinct hormones that regulate a varietyof physiological processes such as cardiac growth, blood pressure,axonal pathfinding and endochondral ossification leading tothe formation of vertebrae and long bones. The biological actionsof NPs are mediated by natriuretic peptide receptors (NPRs)A, B and C that are located on the cell surface. Mutations inNPR-B have been shown to cause acromesomelic dysplasia-typeMaroteaux (AMDM), a growth disorder in humans and severe dwarfismin mice. We hypothesized that missense mutations of NPR-B associatedwith AMDM primarily affect NPR-B function by the arrest of receptortrafficking at the endoplasmic reticulum (ER), due to conformationalchange, rather than an impairment of ligand binding, transmissionof signal through the membrane or catalytic activity. Twelvemissense mutations found in AMDM patients and cn/cn mice weregenerated by site-directed mutagenesis and transiently overexpressedin HeLa cells. Confocal microscopy revealed that 11 out of 12mutants were retained in the ER. Determination of the ligand-dependentcGMP response confirmed that ER-retained NPR-B mutants are non-functional.Meanwhile, the only cell surface-targeted NPR-B missense mutant(D176E) displayed greatly reduced enzymatic activity due toimpaired ligand binding. Thus, in the majority of cases of AMDMassociated with missense NPR-B mutation, disease appears toresult from defects in the targeting of the ER receptor to theplasma membrane.